The present invention relates to the collection and storage of information pertaining to chips for processing biological samples and thereby identifying polymorphisms.
The genomes of all organisms undergo spontaneous mutation in the course of their continuing evolution generating variant forms of progenitor sequences (Gusella, Ann. Rev. Biochem. 55, 831-854 (1986)). The variant form may confer an evolutionary advantage or disadvantage relative to a progenitor form or may be neutral. In some instances, a variant form confers a lethal disadvantage and is not transmitted to subsequent generations of the organism. In other instances, a variant form confers an evolutionary advantage to the species and is eventually incorporated into the DNA of many or most members of the species and effectively becomes the progenitor form. In many instances, both progenitor and variant form(s) survive and co-exist in a species population. The coexistence of multiple forms of a sequence gives rise to polymorphisms.
Despite the increased amount of nucleotide sequence data being generated in recent years, only a minute proportion of the total repository of polymorphisms in humans and other organisms has so far been identified. The paucity of polymorphisms hitherto identified is due to the large amount of work required for their detection by conventional methods. For example, a conventional approach to identifying polymorphisms might be to sequence the same stretch of oligonucleotides in a population of individuals by dideoxy sequencing. In this type of approach, the amount of work increases in proportion to both the length of sequence and the number of individuals in a population and becomes .impractical for large stretches of DNA or large numbers of persons.
Devices and computer systems for forming and using arrays of materials on a substrate have been developed. These devices and systems have been used for identifying polymorphisms. For example, PCT application WO92/10588, incorporated herein by reference for all purposes, describes techniques for sequencing or sequence checking nucleic acids and other materials. Arrays for performing these operations may be formed in arrays according to the methods of, for example, the pioneering techniques disclosed in U.S. Pat. No. 5,143,854 and U.S. Pat. No. 5,571,639, both incorporated herein by reference for all purposes.
According to one aspect of the techniques described therein, an array of nucleic acid probes is fabricated at known locations on a chip or substrate. A fluorescently labeled nucleic acid is then brought into contact with the chip and a scanner generates an image file indicating the locations where the labeled nucleic acids bound to the chip. Based upon the identities of the probes at these locations, it becomes possible to extract information such as the identity of polymorphic forms in of DNA or RNA. Such systems have been used to form, for example, arrays of DNA that may be used to study and detect mutations relevant to cystic fibrosis, the P53 gene (relevant to certain cancers), HIV, and other genetic characteristics.
It would be highly useful to apply such arrays to the study of polymorphisms on a large scale. For example, it would be useful to conduct large scale studies on the correlation between certain polymorphisms and individual characteristics such as susceptibility to diseases and effectiveness of drug treatments. To achieve these benefits, it is contemplated that the operations of chip design, construction, sample preparation, and analysis will occur on a very large scale. The quantity of information related to each of these steps to store and correlate is vast. For large scale polymorphism studies, it will be necessary to store this information in a way to facilitate later advantageous querying and retrieval. What is needed is a system and method suitable for storing and organizing large quantities of information used in conjunction with polymorphism studies.
The present invention provides systems and methods for organizing information relating to study of polymorphisms. A database model is provided which interrelates information about one or more of, e.g, subjects from whom samples are extracted, primers used in extracting the DNA from the subjects, about the samples themselves, about experiments done on samples, about particular oligonucleotide probe arrays used to perform experiments, about analysis procedures performed on the samples, and about analysis results. The model is readily translatable into database languages such as SQL. The database model scales to permit storage of information about large numbers of subjects, samples, experiments, chips, etc.
Applications include linkage studies to determine resistance to drugs, susceptibility to diseases, and study of every characteristic of humans and other organisms that is related genetic variability. Another application of a database constructed according to this model is quality control of the various steps of performing a polymorphism study. By preserving information about every step of a polymorphism study, one can assess the reliability of the results or use the preserved information as feedback to improve procedures.
A further understanding of the nature and advantages of the inventions herein may be realized by reference to the remaining portions of the specification and the attached drawings.